Preparation of Isoxazolin-3-Ylacylbenzene

ABSTRACT

A process is described for preparing isoxazoles of the formula I  
                 
 
     where the substituents are as defined below:  
     R 1  is hydrogen, C 1 -C 6 -alkyl,  
     R 2  is C 1 -C 6 -alkyl,  
     R 3 , R 4 , R 5  are hydrogen, C 1 -C 6 -alkyl, or R 4  and R 5  together form a bond,  
     R 6  is a heterocyclic ring,  
     n is 0, 1 or 2;  
     which comprises preparing an intermediate of the formula VI  
                 
 
     where R1, R3, R4 and R5 are as defined above, followed by halogenation, thiomethylation, oxidation and acylation to give compounds of the formula I.  
     Also novel intermediates for preparing the compounds of the formula I and novel processes for preparing the intermediates are described.

[0001] The present invention provides a process for preparingisoxazolin-3-ylacylbenzenes, novel intermediates and novel processes forpreparing these intermediates.

[0002] Isoxazolin-3-ylacylbenzenes are useful compounds which can beused in the field of crop protection. WO 98/31681, for example,describes 2-alkyl-3-(4,5-dihydroisoxazol-3-yl)acylbenzenes asherbicidally active compounds.

[0003] It is an object of the present invention to provide analternative process for preparing 3-heterocyclyl-substituted benzoylderivatives. The preparation process described in WO 98/31681 for2-alkyl-3-(4,5-dihydroisoxazol-3-yl)acylbenzenes or precursors thereof(2-alkyl-3-(4,5-dihydroisoxazol-3-yl)bromobenzene derivatives) is notparticularly suitable for the industrial preparation of these compounds,since the synthesis involves a plurality of steps and the yield of theend product in question, based on the starting materials employed in thefirst step of the synthesis, is relatively low.

[0004] The preparation of compounds or intermediates with a structuresimilar to that of the compounds of the formula I is known from theliterature:

[0005] WO 96/26206 discloses a process for preparing4-[3-(4,5-dihydroisoxazol-3-yl)benzoyl]-5-hydroxypyrazoles where, in thelast step, a 5-hydroxypyrazole is reacted with a3-(4,5-dihydroisoxazol-3-yl)benzoic acid derivative. The3-(4,5-dihydroisoxazol-3-yl)benzoic acid derivative required for thisprocess can only be obtained with difficulty, via a large number ofsteps. Accordingly, the process is relatively expensive and not optimaleconomically.

[0006] DE 197 09 118 describes a process for preparing3-(4,5-dihydroisoxazol-3-yl)benzoic acids starting from3-bromo-(4,5-dihydroisoxazol-3-yl)benzene, Grignard reagents and carbondioxide. Surprisingly, we have found that the number of process steps inthe preparation of the 3-heterocyclyl-substituted benzoyl derivativescan be reduced compared to the process described in WO 98/31681 if thesynthesis is carried out via selected intermediates. Moreover, theprocess according to the invention has the advantage that the overallyield of the end products of the formula I and also that of theintermediates X, based on the starting materials employed, is higherthan the yield of the processes described in WO 98/31681. Furthermore,the respective intermediates of the individual process steps can beobtained in good yield. Moreover, some of the individual process stepsare advantageous for the industrial preparation of the intermediates,since they allow a cost-effective and economic preparation of thelatter. Furthermore, it is advantageous that the starting materials usedare basic chemicals which are easy to prepare and which can be obtainedfrom several independent suppliers of raw materials, even in relativelylarge amounts. Overall, the process according to the invention providesa more cost-effective, economical and safe industrial process forpreparing herbicidally active compounds of the formula I.

[0007] We have found that the object of the invention is achieved by aprocess for preparing compounds of the formula I

[0008] where the substituents are as defined below:

[0009] R¹ is hydrogen, C₁-C₆-alkyl,

[0010] R² is C₁-C₆-alkyl,

[0011] R³, R⁴, R⁵ are hydrogen, C₁-C₆-alkyl, or R⁴ and R⁵ together forma bond,

[0012] R⁶ is a heterocyclic ring,

[0013] n is 0, 1 or 2;

[0014] which comprises preparing an intermediate of the formula VI

[0015] in which R¹ and R³-R⁵ are as defined above.

[0016] In subsequent reaction steps, compounds of the formula VI areconverted into the corresponding 3-bromo-substituted compounds(bromobenzene derivatives), and the amino group on the phenyl ring istransformed into a sulfonyl group, giving compounds of the formula X:

[0017] The compounds of the formula X(3-(4,5-dihydroisoxazol-3-yl)bromobenzenes) are useful intermediates forpreparing active compounds of the formula I. In particular, the processaccording to the invention affords the compounds I in the last reactionstep in good yield. The compounds I are suitable, for example, for useas crop protection agents, in particular as herbicides, as described inWO 96/26206 and WO 97/35850.

[0018] According to the invention, the compounds of the formula I andthe required intermediates, in particular compounds of the formula VI orX, can be prepared advantageously by combining one or more of thefollowing process steps a)-g):

[0019] a) reaction of a nitro-o-methylphenyl compound of the formula II

[0020] in which the radical R¹ is as defined above with an organicnitrite R—ONO in the presence of a base to give an oxime of the formulaIII

[0021] in which the radical R¹ is as defined above;

[0022] b) cyclization of the oxime of the formula III with an alkene ofthe formula IV

[0023] in which R³ to R⁵ are as defined in claim 1 in the presence of abase to give the isoxazole of the formula V

[0024] in which R¹ and R³ to R⁵ are as defined in claim 1;

[0025] c) reduction of the nitro group in the presence of a catalyst togive the aniline of the formula VI

[0026] in which R¹ and R³ to R⁵ are as defined in claim 1;

[0027] d) reaction of the aniline of the formula VI with a dialkyldisulfide of the formula VII

R²—S—S—R  VII

[0028] in the presence of an organic nitrite R—ONO and, if appropriate,a catalyst to give the thioether of the formula VIII

[0029] in which R¹ to R⁵ are as defined in claim 1;

[0030] e) bromination of the thioether of the formula VIII with abrominating agent to give the bromothioether of the formula

[0031] in which R¹ to R⁵ are as defined in claim 1;

[0032] f) oxidation of the bromothioether of the formula IX with anoxidizing agent to give the isoxazoles of the formula X

[0033] where n is the numbers 1 or 2,

[0034] g) if appropriate reacting the isoxazoline of the formula X witha compound of the formula R⁶—OH (XI) in the presence of carbon monoxide,a catalyst and a base, to give the compounds of the formula I.

[0035] Essentially, the process according to the invention for preparingcompounds X comprises one or more of the process steps a)-f) or, in thecase of the compounds I, one or more of the process steps a)-g).Preference is given to those reaction sequences which comprise eitherone of the process steps a) or d) or else both steps a) and d).

[0036] C₁-C₆-Alkyl and C₁-C₄-alkyl are straight-chain or branched alkylgroups having 1-6 and 1-4 carbon atoms, respectively, such as, forexample, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentylor n-hexyl in all cases. This applies analogously to the C₁-C₆-alkoxygroup.

[0037] R¹ is preferably an alkyl group, in particular methyl, ethyl,isopropyl, n-propyl or n-butyl group [sic].

[0038] R³, R⁴ and R⁵ are preferably hydrogen. R⁴ and R⁵ together mayalso denote a bond, giving rise to the corresponding isoxazolederivatives. In this case, R³ is preferably hydrogen.

[0039] In the definition of R⁶, “heterocyclic ring” means a saturated,unsaturated or partially unsaturated heterocycle having one, two orthree oxygen, sulfur or nitrogen atoms. Preference is given toheterocycles having two nitrogen atoms. In particular, R⁶ is a pyrazoleradical, as described in more detail in WO 98/31681. It is preferably apyrazole which is attached in the 4-position and which may beunsubstituted or substituted by further radicals which are chemicallyinert under the chosen reaction conditions. Suitable pyrazolesubstituents of this type are, for example, the following groups:hydroxyl, oxo, sulfonyloxy, C₁-C₆-alkyl or C₁-C₆-alkoxy, in particularC₁-C₄-alkyl in the 1-position. Particularly preferably, R⁶ is the group1-alkyl-5-hydroxypyrazol-4-yl, in particular1-methyl-5-hydroxypyrazol-4-yl; 1-ethyl-5-hydroxypyrazol-4-yl.

[0040] The process according to the invention is particularly suitablefor preparing the following compounds of the formula I:

[0041]1-methyl-4-(3-(4,5-dihydroisoxazol-3-yl)-2-methyl-4-methylsulfonylbenzoyl)-5-hydroxypyrazole,

[0042]1-ethyl-4-(3-(4,5-dihydroisoxazol-3-yl)-2-methyl-4-methylsulfonylbenzoyl)-5-hydroxypyrazole,

[0043]1-methyl-4-(3-(4,5-dihydroisoxazol-3-yl)-2-ethyl-4-methylsulfonylbenzoyl)-5-hydroxypyrazole,

[0044]1-methyl-4-(3-(4,5-dihydroisoxazol-3-yl)-2-propyl-4-methylsulfonylbenzoyl)-5-hydroxypyrazole,

[0045]1-methyl-4-(3-(4,5-dihydroisoxazol-3-yl)-2-butyl-4-methylsulfonylbenzoyl)-5-hydroxypyrazole.

[0046] Preferred intermediates of the formula VI are the followingcompounds:

[0047] 2-(4,5-dihydroisoxazol-3-yl)aniline,

[0048] 2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline,

[0049] 2-(4,5-dihydroisoxazol-3-yl)-3-ethylaniline,

[0050] 2-(isoxazol-3-yl)-aniline,

[0051] 2-(isoxazol-3-yl)-3-methylaniline,

[0052] 2-(isoxazol-3-yl)-3-ethylaniline:

[0053] Preferred intermediates of the formula X are the followingcompounds:

[0054] 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole,

[0055]3-(3-chloro-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole,

[0056] 3-(3-bromo-6-methylsulfonylphenyl)-4,5-dihydroisoxazole,

[0057] 3-(3-bromo-2-ethyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole,

[0058]3-(3-bromo-2-isopropyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole,

[0059] 3-(3-bromo-2-methyl-6-ethylsulfonylphenyl)-4,5-dihydroisoxazole,

[0060] 3-(3-bromo-2-methyl-6-propylsulfonylphenyl)-4,5-dihydroisoxazole,

[0061] 3-(3-bromo-2-methyl-6-butylsulfonylphenyl)-4,5-dihydroisoxazole,

[0062] 3-(3-bromo-2-methyl-6-pentylsulfonylphenyl)-4,5-dihydroisoxazole,

[0063] 3-(3-bromo-2-methyl-6-hexylsulfonylphenyl)-4,5-dihydroisoxazole.

[0064] A possible reaction sequence up to the preparation of thecompounds X is summarized in the diagram below:

[0065] The individual reaction steps are illustrated in more detailbelow.

[0066] 1. Step a)

[0067] The reaction is carried out, for example under the followingconditions: the solvents used are dipolar aprotic solvents, for exampleN,N-dialkylformamide, N,N-dialkylacetamide, N-methylpyrrolidone (NMP),preferably: dimethylformamide (DMF) or NMP. The temperature is from −60°C. to room temperature; preferably from −50 to −20° C. To achieve asufficiently low melting point of the solvent system, it is alsopossible to use solvent mixtures, for example with THF. The organicnitrites R—ONO used are alkyl nitrites (R=alkyl), preferably n-butylnitrite or (iso)amyl nitrite. Suitable bases are: MOalkyl, MOH, RMgX(M=alkali metal); preferably potassium methoxide (KOMe), sodiummethoxide (NaOMe), or potassium tert-butoxide (KOtbutylate). When usingsodium bases, it is possible to add 1-10 mol % of amyl alcohol. Thestoichiometric ratios are, for example, as follows: 1-4 equivalents ofbase, 1-2 equivalents of R—ONO; preferably: 1.5-2.5 equivalents of baseand 1-1.3 equivalents of R—ONO.

[0068] Addition is, for example, carried out in the following order: a)nitro-o-xylene and nitrite are initially charged and base is metered in.b) To avoid the addition of a solid base, the base can be initiallycharged in DMF, and nitro-o-xylene/butyl nitrite can be addedsimultaneously. The rate at which the base is metered in is relativelyslow, so that the required cooling is reduced to a minimum. Work-up iscarried out by one of the following methods: a) precipitation of theproduct by stirring into water. b) Precipitation of the product byadding a sufficient amount of water to the reaction mixture.Purification of the product is carried out by trituration with tolueneat 0-110° C., preferably at room temperature.

[0069] 2. Step b)

[0070] The reaction is carried out, for example, via the followingmechanistic intermediates: conversion of the oxime III into an activatedhydroxamic acid derivative, for example hydroxamic acid chloride, bychlorination with a chlorinating agent, conversion of the activatedhydroxamic acid derivative into the nitrile oxide, for exampleconversion of the hydroxamic acid chloride in the presence of a baseinto the nitrile oxide, and subsequent cycloaddition of the alkene IV tothe nitrile oxide.

[0071] This reaction is a novel process for preparing isoxazolederivatives of the formula V. Surprisingly, this process affords theisoxazolines in very good yields. Furthermore, only few byproducts areformed, and these can furthermore be removed relatively easily.Accordingly, on an industrial scale, it is easy to isolate and purifythe end products, so that the isoxazolines can be prepared with highpurity and at low cost. The use of known processes for preparingisoxazolines has hitherto been disadvantageous, since the isoxazolinescould only be obtained in unsatisfactory yields starting from thereaction of the benzaldoximes. Furthermore, the processes known from theprior art frequently use alkali metal hypohalide-containing solutionswhich lead to the formation of poorly soluble and environmentallyunfriendly byproducts. The process according to the invention ischaracterized in that the use of alkali metal hypohalide-containingsolutions can be dispensed with, the process thus being essentiallyalkali metal hypohalide-free.

[0072] The isoxazolines are prepared, for example, by the followingmethod: initially, hydroxamic acid chloride is formed which, in a secondstep, is cyclized with an alkene with metered addition of base and, ifappropriate, under superatmospheric pressure. Advantageously, theseindividual steps can also be combined in a “one-pot” reaction. To thisend, the reaction is carried out in a solvent suitable for both partialsteps, for example a carboxylic ester, such as ethyl acetate,chlorobenzene or acetonitrile.

[0073] The preparation of hydroxamic acid chlorides withN-chlorosuccinimide in DMF is known from the literature (Liu et al., J.Org. Chem. 1980; 45: 3916-3918). However, it is also mentioned that theconversion of o-nitrobenzaldoximes into the hydroxamic acid chlorides bychlorination is possible only with poor yields (Chiang, J. Org. Chem.1971, 36: 2146-2155). An expected side-reaction is the formation ofbenzal chloride. Surprisingly, in the process described above,conditions were found which permit the preparation of the desiredhydroxamic acid chlorides in excellent yields. It is particularlyadvantageous that cheap chlorine is used.

[0074] The reaction is carried out, for example, under the followingconditions: solvent: haloalkanes, such as 1,2-dichloroethane ormethylene chloride; aromatic compounds, such as benzene, toluene,chlorobenzene, nitrobenzene or xylene; polar aprotic solvents, forexample N,N-dialkylformamides, -acetamides, N-methylpyrrolidone,dimethylpropyleneurea; tetramethylurea, acetonitrile, propionitrile;alcohols, such as methanol, ethanol, n-propanol or isopropanol;carboxylic acids, such as acetic acid or propionic acid; carboxylicesters, such as ethyl acetate. Preference is given to using thefollowing solvents: acetic acid, methanol, ethanol, 1,2-dichloroethane,methylene chloride, chlorobenzene or ethyl acetate. The reaction iscarried out at from −40° C. to 100° C., preferably from −10 to 40° C. orfrom 0 to 30° C. Suitable for use as halogenating agents are:N-chlorosuccinimide, elemental chlorine, preferably chlorine. Thestoichiometric ratios are, for example, 1-3 equivalents of halogenatingagent, preferably 1-1.5 equivalents. In the case of chlorine, themetered addition is carried out by introducing chlorine gas, andN-chlorosuccinimide (NCS) is metered in as a solid or, if appropriate,in a suitable solvent.

[0075] Work-up is carried out, for example, according to the followingscheme: a) no purification. The solution is directly employed further;b) solvent exchange by distillative removal of the solvent; c) additionof water and extraction of the hydroxamic acid chloride with a suitablesolvent.

[0076] By adding bases, the hydroxamic acid chlorides are converted intothe nitrile oxides. Since the latter compounds are unstable, the problemwhich had to be solved was to find conditions under which the nitrileoxides are stabilized and converted into the desired products.Surprisingly, this problem was solved by selecting the followingreaction conditions: the solvents used are: halogenated alkanes, such as1,2-dichloroethane or methylene chloride; aromatic compounds, such asbenzene, toluene, chlorobenzene, nitrobenzene or xylene; polar aproticsolvents, for example N,N-dialkylformamides, -acetamides,N-methylpyrrolidone, dimethylpropyleneurea; tetramethylurea,acetonitrile, propionitrile, carboxylic esters, such as ethyl acetate.Preference is given to using: 1,2-dichloroethane, methylene chloride,toluene, xylene, ethyl acetate or chlorobenzene.

[0077] The temperatures for the reaction are from 0° C. to 100° C.,preferably 0-50° C. or 0-30° C.

[0078] The bases used are: tertiary amines, for example triethylamine,cyclic amines, such as N-methylpiperidine or N,N′-dimethylpiperazine,pyridine, alkali metal carbonates, for example sodium carbonate orpotassium carbonate, alkali metal bicarbonates, for example sodiumbicarbonate or potassium bicarbonate, alkaline earth metal carbonates,for example calcium carbonate, alkali metal hydroxides, for examplesodium hydroxide or potassium hydroxide. Preference is given to using:triethylamine, sodium carbonate, sodium bicarbonate or sodium hydroxide.

[0079] The stoichiometric ratios are, for example, 1-3 equivalents ofbase, preferably 1-1.5 equivalents; 1-5 equivalents of alkene,preferably 1-2 equivalents. Metered addition is preferably carried outunder a superatmospheric alkene pressure, by slowly adding the base. Thereaction is carried out at from atmospheric pressure to 10 atm,preferably at a pressure of 1-6 atm atmospheric pressure.

[0080] 3. Step C)

[0081] This reaction is a novel, hitherto unknown chemoselectivehydrogenation of a nitro group in the presence of an isoxazoline.Surprisingly, it has been found that, under the chosen reactionconditions, the N—O bond of the isoxazoline ring is not cleaved.Catalytic hydrogenation of aromatic nitro compounds to give the anilineshas been known for a long time (see Houben-Weyl, Vol. IV/lc, p. 506 ff).On the other hand, it is also known that the N—O bond of isoxazoline canbe cleaved by catalytic hydrogenation, for example using Raney nickel(Curran et al., Synthesis 1986, 312-315) or palladium (Auricchio et al.,Tetrahedron, 43, 3983-3986, 1987) as catalyst.

[0082] The reaction is carried out, for example, under the followingconditions: suitable solvents are aromatic compounds, such as benzene,toluene, xylene; polar aprotic solvents, for exampleN,N-dialkylformamides, -acetamides, N-methylpyrrolidone,dimethylpropyleneurea; tetramethylurea, carboxylic esters, such as ethylacetate, ethers, such as diethyl ether or methyl tert-butyl ether,cyclic ethers, such as tetrahydrofuran or dioxane; alcohols, such asmethanol, ethanol, n-propanol or isopropanol, carboxylic acids, such asacetic acid or propionic acid. Preference is given to using thefollowing solvents: ethyl acetate, toluene, xylene, methanol. Thereaction is carried out at temperatures of from −20° C. to 100° C.;preferably of from 0 to 50° C., particularly preferably of from 0 to 30°C. The catalyst used is a platinum or palladium catalyst supported onactivated carbon, with a content of from 0.1 to 15% by weight, based onthe support of activated carbon. If a palladium catalyst is used, it canbe doped with sulfur or selenium to achieve better selectivity.Preference is given to using platinum/activated carbon orpalladium/activated carbon having a Pt- or Pd-content of 0.5-10% byweight.

[0083] The stoichiometric ratios for the reaction are, for example, asfollows: from 0.001 to 1% by weight of platinum or palladium, based onthe nitro compounds: preferably from 0.01 to 1% by weight of platinum.Hydrogen is metered in continuously or batchwise, preferably batchwise,at a pressure of from atmospheric pressure to 50 atm, preferably fromatmospheric pressure to 10 atm.

[0084] The reaction mixture is worked up by removing the catalyst byfiltration. If appropriate, the catalyst can also be re-used. Thesolvent is distilled off. For the subsequent reaction in the nextprocess step, the product can be employed directly without furtherpurification. If required, the product can also be purified further. Theproduct is purified, for example, according to the following scheme: ifrequired, the aniline can be purified by taking it up in dilute mineralacid, for example aqueous hydrochloric acid or dilute sulfuric acid, andextraction with a suitable organic extractant, for example halogenatedalkanes, such as 1,2-dichloroethane or methylene chloride, aromaticcompounds, such as benzene, toluene, chlorobenzene or xylene, ethers,such as diethyl ether or methyl tert-butyl ether, or carboxylic esters,such as ethyl acetate, and be liberated again using a base.

[0085] 4. Step d)

[0086] The reaction is carried out under the following conditions: thesolvents used are, for example: halogenated alkanes, such as1,2-dichloroethane or methylene chloride, aromatic compounds, such asbenzene, toluene, chlorobenzene, nitrobenzene, or an excess of thedialkyl disulfide as solvent. Preference is given to using excessdialkyl disulfide as solvent. The temperature for the reaction is from40° C. to 150° C., preferably from 50 to 100° C., particularlypreferably from 60 to 90° C. The reagents used are organic nitrites(R—ONO), such as, for example, alkyl nitrites, preferably n-butylnitrite, (iso)amyl nitrite or tert-butyl nitrite. Here, R is anyorganic, chemically inert radical which does not have any effect on theactual reaction. R is, for example, a C₁-C₆-alkyl or C₂-C₆-alkenylgroup.

[0087] In the reaction of the compounds, the stoichiometric ratios are,for example, as follows: 1-3 equivalents of alkyl nitrite, preferably1-1.5 equivalents of alkyl nitrite. The following catalysts may be used:copper powder, elemental copper in a different form, such as, forexample, turnings, wire, granules, pellets, rods; copper(I) salts, forexample copper(I) chloride, copper(I) bromide or copper(I) iodide,copper(II) salts, or elemental iodine, particularly preferably copperpowder. When carrying out the reaction in the solvent, 1-3 equivalentsof dialkyl disulfide, preferably 1-2 equivalents, are employed. In apreferred embodiment, an excess of dialkyl disulfide is employed assolvent and then recovered by distillation. For further reactions, theproduct can be used without further purification. If appropriate, it isalso possible to purify the product beforehand by distillation orcrystallization using suitable solvents, for example from diisopropylether.

[0088] 5. Step e)

[0089] The bromination is carried out similarly to the method describedin WO 98/31676. Acetic acid is an advantageous solvent.

[0090] 6 Step f

[0091] The oxidation is carried out similarly to the method described inWO 98/31676 (cf. p. 8, line 32 to p. 11, line 25).

[0092] 7. Step g)

[0093] The optional subsequent conversion of the compound of the formulaX into compounds of the formula I is carried out by adding R⁶—OH (XI) inthe presence of carbon monoxide and a suitable catalyst and a base. IfR⁶ is an unsubstituted or substituted pyrazole or pyrazolone ring, thereaction is preferably carried out using palladium-containing catalysts,such as, for example, Pd(0) catalyst orbis(triphenylphosphine)palladium(II) chloride.

[0094] The process mentioned in step g) is a novel and advantageousprocess for preparing compounds of the formula I which are obtainedstarting from halophenyl derivatives X by acylation or carboxylationwith hydroxy-substituted heterocycles of the formula R⁶—OH (XI).

[0095] EP-A 344 775 discloses a process for preparing4-benzoyl-5-hydroxypyrazoles in one step where the synthesis is carriedout starting from bromobenzenes and 5-hydroxypyrazoles in the presenceof carbon monoxide, base and catalyst. The benzoyl radical of the targetmolecules may carry the following substituents in the 3-position:alkoxycarbonyl, alkoxy, alkoxymethyl. These substituents are consideredto be relatively stable or inert chemically and allow the use of thedrastic reaction conditions of the working examples. In contrast, thepreparation of benzoyl-5-hydroxypyrazoles which carry less stablesubstituents in the 3-position, as is the case, for example, for theisoxazole or isoxazoline radical, are not described in EP 344 775, withrespect to the drastic reaction conditions. In particular, owing to itsredox properties, the isoxazole or isoxazoline radical is considered tobe a highly sensitive radical. A further disadvantage of the processknown from EP-A 344 775 is the fact that the 5-hydroxypyrazole is alwaysemployed in a large excess.

[0096] Below, the process is illustrated in more detail, using theexample where R⁶=pyrazole (XI.a) as heterocycle. However, in principle,it is also possible to use other heterocyclic compounds, as defined atthe outset.

[0097] The process is preferably carried out by reacting ahydroxypyrazole of the formula XI.a

[0098] in which R⁷ is C₁-C₆-alkyl and M is hydrogen or an alkali metalatom, preferably sodium or potassium, and a bromobenzene of the formulaX

[0099] in which R¹ to R⁵ are as defined above, in the presence of carbonmonoxide, a palladium catalyst, if appropriate at least one molarequivalent of a potassium salt and if appropriate at least one molarequivalent of a tertiary amine of the formula XIII

N(R_(a))₃  XIII

[0100] in which one of the radicals R_(a) may represent phenyl ornaphthyl and the other radicals R_(a) are C₁-C₆-alkyl, at temperaturesof from 100 to 140° C. and a pressure of from 1 to 40 kg/cm².

[0101] In a preferred embodiment of the process, the 5-hydroxypyrazoleXI.a and the bromobenzene derivative X are employed in a molar ratio offrom 1 to 2.

[0102] Preference is given to using, as 5-hydroxypyrazole XI.a,compounds in which R⁷ is C₁-C₆-alkyl, in particular methyl or ethyl.

[0103] The 5-hydroxypyrazoles (or pyrazolinones) of the formula XI.aused as starting materials are known and can be prepared by processesknown per se (cf. EP-A 240 001, WO 96/26206 and J. Prakt. Chem. 315(1973), 382).

[0104] In general, the 5-hydroxypyrazole XI.a is employed in equimolaramounts or in excess, based on the bromobenzene derivative X. Forreasons of economy, it makes sense to avoid a relatively large excess of5-hydroxypyrazole. Under the reaction conditions according to theinvention, the stoichiometric reaction gives the same yield as thatwhich is obtained if an excess of 5-hydroxypyrazole is used. This wassurprising, since a large excess of 5-hydroxypyrazole is used in all ofthe examples of the process described in EP-A 344 775. In the processaccording to the invention, the molar ratio of 5-hydroxypyrazole tobromobenzene is preferably adjusted to 1-2 and particularly preferablyto 1.0-1.2.

[0105] Above 140° C., decomposition occurs, and below 100° C., thereaction comes to a halt. The reaction is therefore generally carriedout in a temperature range of from 100 to 140° C., preferably from 110to 130° C.

[0106] Surprisingly, it has been found that the high pressure in therange of up to 150 kg/cm² normally required for the reaction (cf. thedetails given in EP 344 775) can be reduced to a value of at most up to40 kg/cm², preferably to up to 20 kg/cm² or else up to 10 kg/cm²,without this having an adverse effect on the reaction conditions, suchas reaction temperature or reaction time, or resulting in a loss ofyield. The reaction pressure is preferably at least 3 kg/cm², inparticular at least 5 kg/cm². Suitable pressure ranges are, for example:1-40 kg/cm², 5-20 kg/cm² or 10-20 kg/cm², in particular 3-10 andparticularly preferably 5-8 kg/cm².

[0107] This pressure reduction is particularly advantageous if thepreparation process is to be carried out on an industrial scale, sincethe safety requirements which have to be met with respect to thepressure vessels used are less stringent. Thus, the costly use ofhigh-pressure vessels can be dispensed with. Accordingly, thepreparation process described in g) is safer and more economical.

[0108] Furthermore, it has surprisingly been found that the palladiumcompounds used as catalysts are, under the chosen reaction conditions,mainly obtained as elemental palladium and can be removed from thereaction mixture in a simple manner by filtration. Thus, concentrationof the palladium-containing reaction solution for subsequent disposal,which is complicated and costly, and any incineration of the residuescan substantially be dispensed with. This reduces recycling costs. Thepore size of the precipitated palladium is 1-10 μm, in particular 1-4μm. The palladium filtered off in this way can be worked up at low costto give the corresponding palladium compounds, such as, for example,palladium chloride, since the recycling costs depend on the palladiumconcentration.

[0109] Suitable solvents for the reaction in process step g) arenitrites, such as benzonitrile and acetonitrile, amides, such asdimethylformamide, dimethylacetamide, tetra-C₁-C₄-alkylureas orN-methylpyrrolidone, and preferably ethers, such as tetrahydrofuran andmethyl tert-butyl ether. Particularly preferred solvents are ethers suchas 1,4-dioxane and dimethoxyethane.

[0110] Suitable catalysts are palladium-ligand complexes in which thepalladium is present at the oxidation state 0, metallic palladium, ifappropriate on a support, and preferably palladium(II) salts. Thereaction with palladium(II) salts and metallic palladium is preferablycarried out in the presence of complex ligands.

[0111] A suitable palladium(0)-ligand complex is, for example,tetrakis(triphenylphosphane)palladium.

[0112] Metallic palladium is preferably absorbed on an inert carrier,such as, for example, activated carbon, silica, alumina, barium sulfateor calcium carbonate. The reaction is preferably carried out in thepresence of complex ligands, such as, for example, triphenylphosphane.

[0113] Suitable palladium(II) salts are, for example, palladium acetateand palladium chloride. The reaction is preferably carried out in thepresence of complex ligands, such as, for example, triphenylphosphane.

[0114] Suitable complex ligands for the palladium-ligand complexes, orthose in whose presence the reaction with metallic palladium orpalladium(II) salts is preferably carried out, are tertiary phosphaneswhose structure is represented by the formulae below:

[0115] where n is a number from 1 to 4 and the radicals R⁸ to R¹⁴ areC₁-C₆-alkyl, aryl-C₁-C₂-alkyl or, preferably, aryl. Aryl is, forexample, naphthyl and unsubstituted or substituted phenyl, such as, forexample, 2-tolyl, and in particular unsubstituted phenyl.

[0116] The complex palladium salts can be prepared in a manner known perse starting from commercially available palladium salts, such aspalladium chloride or palladium acetate, and the correspondingphosphanes, such as, for example, triphenylphosphane or1,2-bis(diphenylphosphano)ethane. Many complex palladium salts are alsocommercially available. Preferred palladium salts are[(R)(+)2,2-bis(diphenylphosphano)-1,1′-binaphthyl]palladium(II)chloride, bis(triphenylphosphane)palladium(II) acetate and, inparticular, bis(triphenylphosphane)palladium(II) chloride.

[0117] In general, the palladium catalyst is employed in a concentrationof from 0.05 to 5 mol %, preferably from 1 to 3 mol %.

[0118] Amines N(R_(a))₃ of the structure XIII which are suitable for theprocess are tertiary amines, such as, for example, N-methylpiperidine,ethyldiisopropylamine, 1,8-bisdimethylaminonaphthalene or, inparticular, triethylamine.

[0119] Suitable potassium salts are, for example, potassium phosphate,potassium cyanide and, in particular, potassium carbonate.Advantageously, the water content of the potassium salt should be low.For this reason, the potassium carbonate was, prior to use, generallydried at at least 150° C.

[0120] The amount of potassium salt used is advantageously at least 1molar equivalent. Otherwise, the reaction rate will be reduced, or theintermediate Fries rearrangement does not proceed completely, andO-acylated pyrazole derivatives are obtained. Preferably, in each casefrom 2 to 4 molar equivalents and particularly preferably 2 molarequivalents of potassium salt are employed, based on the bromobenzeneIII.

[0121] In addition to the potassium salt, the reaction mixture ispreferably also admixed with an amine N(R_(a))₃ of the formula XIII inwhich one of the radicals R_(a) may be phenyl or naphthyl and the otherradicals R_(a) are C₁-C₆-alkyl. Preferably, 1 to 4 molar equivalents,particularly preferably 2 molar equivalents, of the amine XIII areemployed, based on the bromobenzene X.

[0122] For work-up, the reaction solution is usually introduced intowater. If the reaction is carried out in a water-miscible solvent, suchas 1,4-dioxane, it may be advantageous to remove beforehand some or allof the solvent from the reaction mixture, if appropriate under reducedpressure. Any solid components are then removed from the aqueousalkaline reaction mixture, and a pH of from 2.5 to 4.5, preferably 3.5,is established by acidification with a mineral acid, such as, forexample, hydrochloric acid, resulting in virtually completeprecipitation of the product of value. The isoxazoline radical, inparticular, is sensitive to hydrolysis. In processes for preparingbenzoylpyrazoles which contain this radical, a pH of below 2 shouldpreferably be avoided.

[0123] The acylation in process step g) is preferably carried out underthe following process conditions: solvent: dioxane or mixtures ofdioxane and acetonitrile. Temperature: 110-130° C. Pressure: 5-8,preferably about 6, kg/cm². Catalyst: palladium(II) chloride. Molarratio of the heterocyclic hydroxy compounds (such as, for example,5-hydroxypyrazole) to bromobenzene derivatives: from 1 to 2 andparticularly preferably from 1.0 to 1.2.

[0124] Alternatively to the synthesis route shown in scheme 1, thecompounds of the formula X can also be prepared according to schemes 2and 3 below.

[0125] Scheme 2 shows a possible synthesis route to bromobenzenederivatives of the type of formula X using the synthesis of3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydro-isoxazole asan example. The individual process steps can be carried out followingcustomary standard methods.

[0126] The bromination of compounds of the formula VI is carried outsimilarly to the direct bromination of anilines. If the reagent used istetrabutylammonium tribromide, it is in some cases possible to achieveselective monobromination in the position para to the amine function(Berthelot et al., Synth. Commun. 1986, 16: 1641). However, a generalproblem in such brominations is the formation of polybrominated products(Bull. Chem. Soc. Jpn. 1988, 61: 597-599). Thus, for example, thereaction of VI with tetrabutylammonium tribromide in a methanol/watermixture with calcium carbonate as base gives a product mixturecontaining about 25% of dibrominated byproduct. The separation of theproduct mixture is critical in particular when the substituents includeisoxazole or isoxazoline radicals which, with a view to their redoxproperties, are considered as being labile under the chosen reactionconditions.

[0127] We have now found conditions which allow the desired product XIVto be prepared in good yields, without more highly brominated byproductsbeing formed. According to the reaction conditions of the invention, thepreferred reagent is tetrabutylammonium tribromide. The solvents usedare haloalkanes, such as 1,2-dichloroethane or methylene chloride,alcohols, such as methanol, ethanol, n-propanol, isopropanol, oraliphatic nitrites, such as acetonitrile, preferably acetonitrile. Thepreferred base base [sic] is potassium carbonate. The brominatedintermediates XIV can then be converted into theisoxazol-3-ylbromobenzenes X according to the invention by variousroutes. The intermediates for preparing compounds IX from XIV orcompounds X from IX can be prepared by the processes already mentionedabove.

[0128] However, it is alternatively also possible to convert theanilines initially into the sulfonyl chlorides X.c (see Houben-Weyl,Vol. TX, pp. 575-580). The sulfonyl chlorides can be converted byreduction, for example using sodium sulfide, via the sulfinic acid stage(see Houben-Weyl, Vol. IX, pp. 306-307) and subsequent alkylation (seeHouben-Weyl, Vol. IX, pp. 231-233), into the alkyl sulfones. The twosteps can advantageously be combined in a “one-pot reaction”. Thissynthesis has the advantage that favorable starting materials are usedfor introducing the alkylsulfonyl groups.

[0129] The oximation of substituted toluenes, used in process step a) ofthe process according to the invention, is a novel and advantageousmethod for converting toluene derivatives into benzaldoximes. Inprinciple, this method is suitable for preparing benzaldoximes of theformula XV

[0130] in which the radicals are as defined below:

[0131] X is NO₂, S(O)_(n)R_(y),

[0132] Rx is any inert radical;

[0133] Ry is any inert radical;

[0134] m is 0, 1, 2, 3 or 4,

[0135] n is 0, 1 or 2.

[0136] Rx and Ry are any organic radicals which can be identical ordifferent and are inert under the chosen reaction conditions. Rx may,for example, be: halogen, such as, for example, chlorine, bromine oriodine; carboxyl; carboxamide; N-alkylcarboxamides andN,N-dialkylcarboxamides; phenyl; C₁-C₆-alkyl, such as, for example,methyl, ethyl; C₁-C₆-alkoxy; C₁-C₆-alkylthio or other radicals. If m>1,Rx can in each case be identical or different. Rx preferably has thesame meaning as R¹ and is located ortho to the oxime group —CH═NOH. mis, in particular, the number 2, one of the substituents Rx having thesame meaning as R¹ and the second substituent Rx being a halogen atomwhich is preferably located meta to the oxime group. Ry is preferablyC₁-C₆-alkyl, for example methyl, ethyl, propyl.

[0137] Preferred compounds XV are those in which X is the group SO₂-Ryand m is the number 2. In this case, one of the radicals Rx ispreferably halogen (for example bromine or chlorine) and is located metato the oxime group. The second radical Rx is preferably C₁-C₆-alkyl (forexample methyl, ethyl) and is located ortho to the oxime group.

[0138] According to the invention, compounds of the formula XVI(o-nitrotoluene or o-alkylsulfonyltoluene)

[0139] in which the substituents are as defined above are reacted withan organic nitrite of the formula R—O—NO, as already defined, in thepresence of a base.

[0140] The nitrosation of o-nitrotoluene has been described in theliterature (Lapworth, J. Chem. Soc. 79 (1901), 1265). However, even inthis early work, a dimeric byproduct is mentioned. Later works onlydescribe the preparation of dimeric products under similar reactionconditions (Das et al., J. Med. Chem. 13 (1970), 979). Repetition of theexperiment described in the literature using o-nitrotoluene shows that,indeed, the 2-nitrobenzaldoxime is formed in small amounts.

[0141] When the conditions described were applied to 3-nitro-o-xylene,only the dimer XVIII was formed.

[0142] For Michael additions, which proceed under similar conditions,the literature likewise mentions that they do not succeed with3-nitro-o-xylene (Li, Thottathil, Murphy, Tetrahedron Lett. 36 (1994),6591). From what has been described, it would therefore not be expectedthat benzaldoximes can be prepared in excellent yields from6-substituted 2-nitrotoluene. Moreover, it has surprisingly been foundthat alkylsulfonates (X═SO₂Ry) can, under comparable conditions,likewise be oximated at the methyl group in the opposition. Thecompounds prepared by the process according to the invention areimportant intermediates in the production of active compounds for cropprotection agents (WO 98/31681).

[0143] The reaction is preferably carried out under the followingconditions:

[0144] The solvents used are: dipolar aprotic solvents, for exampleN,N-dialkylformamide, N,N-dialkylacetamide, N-methylpyrrolidone,preferably DMF, NMP. The temperature is from −60° C. to roomtemperature; preferably from −50 to −20° C. The preferred nitrite oralkylnitrite is n-butyl nitrite and (iso)amyl nitrite. Suitable basesare: (M=alkali metal): MOalkyl, MOH, RMgX; preferably KOMe, NaOMe,KOt-butoxide. If sodium bases are employed, preference is given toadding 1-10 mol % of amyl alcohol. The stoichiometry is as follows: 1-4equivalents of base, 1-2 equivalents of RONO; preferably: 1.5-2.5equivalents of base, 1-1.3 equivalents of RONO (i.e. an organicnitrite). The order of addition: a) nitro-o-xylene and nitrite areinitially charged and base is metered in. b) To avoid having to meter inthe base as a solid, it is possible to initially charge the base in DMFand to add nitro-o-xylene/butyl nitrite simultaneously. It isadvantageous to meter in the base over a relatively long period of time,to reduce the required cooling.

[0145] Work-up is carried out, for example, as follows: a) precipitationby stirring the mixture into water/acid. b) Precipitation by adding asufficient amount of water/acid. Suitable acids are mineral acids, suchas sulfuric acid, hydrochloric acid or phosphoric acid, or elsecarboxylic acids, such as acetic acid. Purification of the product: bytrituration with toluene at from 0 to 110° C., preferably at roomtemperature.

[0146] If the reaction is carried out at a relatively high temperature(from −10 to 0° C.), followed by additional stirring at roomtemperature, work-up affords the benzonitriles directly. Furthermore, itis possible to release the aldehyde function from the benzaldoximes ofthe formula XV in the presence of an acidic catalyst and an aliphaticaldehyde, for example aqueous formaldehyde solution. Suitable solventsare halogenated alkanes, such as 1,2-dichloroethane or methylenechloride, aromatic compounds, such as benzene, toluene, chlorobenzene,nitrobenzene or xylene, polar aprotic solvents, for exampleN,N-dialkylformamides, -acetamides, N-methylpyrrolidone,dimethylpropyleneurea; tetramethylurea, tetrahydrofuran, acetonitrile,propionitrile or acetone, if appropriate with addition of water.Particularly advantageous are aqueous acetone (1 to 20% of water),dioxane/water mixtures and tetrahydrofuran/water mixtures. The reactionis carried out at temperatures from room temperature to the refluxtemperature of the solvent, preferably from 30 to 70° C. Suitable acidsare mineral acids, such as aqueous hydrochloric acid, sulfuric acid orphosphoric acid, and acidic ion exchangers, such as Amberlyst 15 orDowex 50W x 8.

[0147] In the case of the compounds of the formula XV, the oxime group—CH═NOH can then be converted into the corresponding aldehydes (—CHO) orelse into the corresponding nitrites (—CN). These compounds areimportant synthesis building blocks for preparing active compounds ofthe formula I (cf. WO 98/31681).

[0148] The thioalkylation step employed in process step d) of theprocess according to the invention is a novel and advantageous methodfor converting aniline derivatives into thioether derivatives(thioalkylation of aniline derivatives). In principle, the method isgenerally suitable for preparing thioethers of the formula XIX

[0149] where Rx is any inert radical, m is a number from 0 to 5 and R²is a C₁-C₆-alkyl group, which comprises reacting an aniline of theformula XX

[0150] with a dialkyl disulfide of the formula VII

R²—S—S—R²  VII

[0151] in the presence of a catalyst. Preferred catalysts are copperpowder, in particular copper powder having a particle size of below 70μm, or elemental copper in another form, such as, for example, turnings,wire, granules, pellets or rods.

[0152] In the compounds of the formula XIX and XX, Rx is any radicalwhich is chemically inert under the chosen reaction conditions duringthe reaction with compounds of the formula VII. In this sense, suitableRx groups are, for example: hydrogen, alkyl, haloalkyl, halogen, cyano,nitro, alkoxy, haloalkoxy, alkylthio or heterocyclic radicals asmentioned at the outset in the definition of R⁶. A heterocyclic radicalis, in particular, an unsubstituted or alkyl-substituted 5-memberedheterocyclic saturated, partially saturated or aromatic ring from thegroup of the isoxazolines, isoxazoles, thiazolines, thiazoles, oxazolesand pyrazoles. The compounds of the formula XIX and XX may carry one ormore, preferably one, two or three, substituents Rx, which may beidentical or different.

[0153] Rx is preferably a C₁-C₆-alkyl group, for example methyl, ethylor propyl. m is preferably the number 1 or 2. If m is the number 1, Rxis preferably ortho or meta to the group —S—R² (in the case of compoundsXIX) or to the amino group (in the case of the compounds XX). If m isthe number 2, the second radical Rx is preferably ortho and meta to thegroup —S—R² or to the amino group.

[0154] Thioethers of the formula XIX are useful intermediates forpreparing active compounds in the chemical industry, for example forpreparing crop protection agents (for example WO 96/11906; WO 98/31676)or for preparing medicaments. A process which is frequently used forintroducing alkylthio functions is the exchange of a halogen (EP 0 711754). However, the process described in this publication has thedisadvantage that it is limited to aromatic compounds which aresubstituted by radicals which are strongly electron-withdrawing.Moreover, the preparation frequently requires high temperatures. Underthese reaction conditions, other sensitive functional groups arechemically modified, resulting in complex reaction mixtures which aredifficult and costly to purify, or where in certain cases removal of theimpurities is not possible at all. In addition, suitable precursors arenot always commercially available.

[0155] Methods for preparing arylalkyl sulfides from anilines are known,but these methods have serious disadvantages. The Sandmeyer reaction,for example, requires the use of equimolar amounts of copper alkylthiolate (Baleja, Synth. Commun. 14 (1984), 215-218). The yields thatare obtained are typically only in the range of from 20 to 60%.

[0156] A further method that has been described is the reaction ofaromatic amines with alkyl nitrites in excess dialkyl sulfide (Giam etal., J. Chem. Soc., Chem. Commun 1980, 756-757). Here, it is a problemthat, in some cases to a considerable extent, side-reactions occur,resulting in poor yields and a high expense in the purification of theproduct. Moreover, it was observed that, if the reaction is carried outin an inert diluent, a very vigorous reaction which was difficult tocontrol set in after an induction phase, thus excluding use on anindustrial scale. It is an object of the present invention to provide analternative process for the preparation of thioethers. Using thepreparation process according to the invention, it is possible toprepare aromatic alkyl thioethers advantageously from anilines. Usingthe process, it is possible to carry out the preparation in a simplemanner, at low cost and efficiently, taking into account ecologicallyand economically advantageous aspects.

[0157] According to the invention, the reaction of the aniline with adialkyl disulfide and an organic nitrite R—ONO is carried out accordingto the reaction scheme shown above, in the presence of a catalyst,preferably elemental copper. Comparative experiments have shown that,under the conditions according to the invention, considerably betteryields are obtained and fewer byproducts are formed than when nocatalyst is used. Moreover, the reaction is easy to control and suitablefor use on an industrial scale.

[0158] The reaction is carried out under the reaction conditionsspecified in more detail below: suitable solvents are halogenatedalkanes, such as 1,2-dichloroethane or methylene chloride, or aromatics,such as benzene, toluene, chlorobenzene or nitrobenzene. Alternatively,it is also possible to use an excess of dialkyl disulfide itself assolvent. This variant is particularly advantageous. The temperatures forthe reaction are from 40° C. to 150° C., preferably from 60 to 100° C.and in particular from 70 to 90° C. In the reaction, it is advantageousto add a C₁-C₆-alkyl nitrite reagent. Suitable for this purpose are, forexample, n-butyl nitrite, (iso)amyl nitrite and tert-butyl nitrite. Inthis case, the stoichiometry is, for example, 1-3 equivalents of alkylnitrite, preferably 1-1.5 equivalents of alkyl nitrite. Suitablecatalysts are copper powder or elemental copper in another form,copper(I) salts, for example copper(I) chloride, copper(I) bromide orcopper(I) iodide, copper(II) salts, or elemental iodine, preferablycopper powder or elemental copper in another form. The reaction is, forexample, carried out under the following stoichiometric ratios: if thereaction is carried out in a solvent: 1-3 equivalents of dialkyldisulfide, preferably 1-2 equivalents. If the reaction is carried outwithout additional solvent, i.e. if the dialkyl disulfide is used assolvent: an excess of dialkyl disulfide or of a dialkyl disulfidemixture is used, subsequent distillative recovery being possible. Theproduct is purified, for example, by distillation or crystallization(for example from diisopropyl ether).

[0159] The present invention furthermore provides a process forpreparing compounds X using the process described above for theoximation of substituted toluenes XVI (cf. process step a)) and/or usingthe process described above for the thioalkylation of anilinederivatives XX (cf. process step d)). In reaction scheme 4 below, asuitable preparation process is described using the example of acompound X where R¹═CH₃, R²═CH₃, R³═R⁴═R⁵═H. In principle, the processis also suitable for preparing compounds X where the radicals R¹—R⁵ areas defined above.

[0160] The invention is illustrated in more detail in the workingexamples below. Examples 1-9 relate to process steps a)-g) Examples10-26 relate to the preparation of starting materials or intermediates,or are corresponding comparative examples. Example 27 relates to thereaction sequence for preparing compounds X, shown in scheme 4.

EXAMPLE 1

[0161] Preparation of 2-methyl-6-nitrobenzaldoxime

[0162] (process step a)-variant A)

[0163] A solution of 274 g (2.6 mol) of n-butyl nitrite (97%) and 300 g(2.0 mol) of 3-nitro-o-xylene (97%) in 750 ml of dimethylformamide iscooled to from −55 to −60° C., and a solution of 522 g (4.56 mol) ofpotassium tert-butoxide in 750 ml of dimethylformamide is added dropwiseat this temperature over a period of 2.5 hours. During the addition, thecolor of the solution changes from yellow to deep red and the solutionbecomes viscous. The reaction is monitored by HPLC. For work-up,initially 300 ml of water are added and then about 300 ml of glacialacetic acid, until the pH has reached 5-6. During the addition, thetemperature increases to −10° C., and a yellow suspension is formed. Thereaction mixture is then poured onto 6 kg of ice-water and the residuethat has formed is filtered off with suction, washed with 5 l of waterand dried in a drying cabinet at 30° C. overnight.

[0164] This gives 339 g of a light-beige crude product which is freedfrom the impurities by suspension in about 3 l of toluene at 80-90° C.for 2 hours. After cooling, the product is filtered off with suction anddried. This gives 276 g of 2-nitro-6-methyl-benzaldoxime.

[0165] Yield: 77%, m.p.: 190-192° C., purity (according to HPLC): 98%.

EXAMPLE 2:

[0166] Preparation of 2-methyl-6-nitrobenzaldoxime

[0167] (process step a)-variant B)

[0168] 1200 ml of anhydrous DMF are initially charged in a 4 l reactionflask and cooled to −40° C. At this temperature, 336.5 g (4.56 mol) ofpotassium methoxide (95%) are added and suspended with stirring. Amixture of 300 g (1.92 mol) of 3-nitro-o-xylene (97%) and 274 g (2.52mol) of n-butyl nitrite (95%) is then added dropwise at −40° C. over aperiod of 7 hours (if the mixture is cooled accordingly, the duration ofthis addition can be reduced as desired; a longer period of addition hasnot yet been tested; temperature variations between −35 and −45° C. aretolerated). The complete conversion of the starting material is checkedby HPLC. The reaction discharge is then added with stirring, at from −5to 0° C., to a mixture of 300 ml of water and 300 ml of glacial aceticacid. The reaction mixture is then poured onto 6 kg of ice-water and thesolid is separated off by filtration (without any problems, filterresistance has not yet been determined) and washed twice with in eachcase 500 ml of water (careful: the crude product smells strongly). Thecrude product (HPLC: 96 area %) is purified by suspending the moistsolid in 800 ml of toluene for 1.5 h. The solid is filtered off (withoutany problems, the filter resistance has not yet been determined) anddried at 50° C. in a vacuum drying cabinet.

[0169] Yield: 306 g (HPLC: 99.4 area % of product; E/Z mixture),corresponds to 85% of theory.

EXAMPLE 3

[0170] Preparation of 3-(2-methyl-6-nitrophenyl)-4,5-dihydroisoxazole(process step b))

[0171] a) At 60° C., a small amount of a solution of 3.71 g (28 mmol) ofN-chlorosuccinimide in 30 ml of acetonitrile is added to a solution of 5g (28 mmol) of 2-methyl-6-nitrobenzaldoxime in 50 ml of acetonitrile.Once the reaction has started, the remainder of the solution is slowlyadded dropwise at 40-50° C. The mixture is stirred for an extra 20minutes, until the conversion is complete by HPLC. This gives an orangesolution which is carefully concentrated. The residue is suspended in 50ml of toluene for about 1.5 hours and the solution is separated from thesuccinimide. The filtrate is still orange-red. The solution is filledinto a mini autoclave, and an ethylene pressure of 30 bar is appliedover a period of 5 hours, a solution of 4.7 g of sodium bicarbonate in50 ml of water is then metered in, and the mixture is stirred at anethylene pressure of 30 bar for another 5 hours. For work-up, the phasesare separated and the toluene phase is washed 2×with NaHCO₃ solution and1×with water, dried and concentrated. Yield: 4.9 g (86%), brownishcrystals, m.p.: 100-105° C.

[0172]¹H-NMR (CDCl₃): δ=8.00 (d, 1H); 7.57 (d, 1H); 7.49 (t, 1H);

[0173] 4.60 (t, 2H); 3.32 (t, 2H); 2.41 (s, 3H).

[0174] b) 100 g of 2-methyl-6-nitrobenzaldoxime are dissolved in 750 mlof glacial acetic acid, and chlorine is then introduced for 2 hours.Excess chlorine is flushed out with nitrogen. The glacial acetic acid isthen distilled off and the residue is 45 suspended in 1000 ml oftoluene. The reaction mixture is filled into the autoclave, and anethylene pressure of 6 bar is applied. Over a period of one hour, 55.6 gof triethylamine (1 equivalent) in 300 ml of toluene are metered in, andthe mixture is stirred at room temperature and under 6 bar of ethylenefor 10 h. The mixture is washed once with saturated aqueous NaHCO₃solution and once with water. The organic phase is dried over sodiumsulfate, filtered off and concentrated using a rotary evaporator. Yield:96.3 g (87% of theory).

EXAMPLE 4

[0175] Preparation of 2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline(process step c))

[0176] a) A solution of 117 g (0.57 mol) of3-(2-methyl-6-nitrophenyl)-4,5-dihydroisoxazole in 1.2 l of ethylacetate and 11.7 g of a catalyst containing 5% by weight of platinum oncarbon are added to a hydrogenation autoclave. The autoclave is thenflushed twice with nitrogen. At a hydrogen pressure of 20 bar, themixture is then hydrogenated at 25-30° C. for 48 hours, with vigorousstirring. The reaction discharge is filtered off with suction throughsilica gel and the solvent is stripped off under reduced pressure. Thisgives 94 g of a brown solid which is taken up in methyl tert-butyl etherand water and extracted with 1M hydrochloric acid. The aqueous phase isadjusted to pH 10-11 and extracted with methylene chloride. Themethylene chloride phase is dried over magnesium sulfate and the solventis stripped off.

[0177] Yield 87 g (87%) of an orange solid, m.p.: 86-88° C., purityaccording to HPLC 97%.

[0178] The product can be purified further by stirring with methyltert-butyl ether at reflux: m.p.: 90-91° C., purity according to HPLC100%.

[0179] b) A solution of 1000 g (4.85 mol) of3-(2-methyl-6-nitrophenyl)-4,5-dihydroisoxazole in 5.5 l of methanol and4.6 g of a catalyst containing 10% by weight of palladium on carbon areadded to a hydrogenation autoclave. The autoclave is then flushed twicewith nitrogen. At a hydrogen pressure of 2.5 bar, the mixture is thenhydrogenated at 25-30° C. for 17 hours, with vigorous stirring. Thereaction discharge is filtered off with suction through silica gel andthe solvent is stripped off under reduced pressure.

[0180] This gives 781.7 g of a light-brown solid.

[0181] Yield 781.7 g (85%) (content according to HPLC 93%).

EXAMPLE 5

[0182] Preparation of3-(2-methyl-6-methylthiophenyl)-4,5-dihydroisoxazole (process step d))

[0183] 19.5 g (170 mmol) of tert-butyl nitrite and 20 g of copper powderare initially charged in 30 ml of dimethyl disulfide, and a solution of20 g (114 mmol) of 2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline in 100ml of dimethyl disulfide is added dropwise at from 50 to 55° C. Themixture is then stirred at 60° C. for 1.5 hours. For work-up, the solidis filtered off with suction and the solution is diluted with methylenechloride and extracted with dilute hydrochloric acid. The organic phaseis washed with saturated aqueous NaHCO₃ solution, dried over sodiumsulfate, filtered off and concentrated. Excess dimethyl disulfide isremoved under oil pump vacuum.

[0184] This gives 23.4 g (99%) of a dark oil which solidifies after awhile. (Content according to HPLC 100%). The product can be purifiedfurther by stirring in methyl tert-butyl ether. M.p.: 66-67° C.

EXAMPLE 6

[0185] Preparation of3-(3-bromo-2-methyl-6-methylthiophenyl)-4,5-dihydroisoxazole (processstep e))

[0186] At 0° C., 10 g (48 mmol) of3-(2-methyl-6-methylthiophenyl)-4,5-dihydroisoxazole are added a littleat a time to 120 ml of conc. sulfuric acid, and the mixture is stirredfor about 30 minutes. 3.7 g (23 mmol) of bromine are then addeddropwise, and the mixture is stirred at 0° C. for 2.5 hours. The mixtureis then allowed to warm to room temperature over a period of about 45minutes. A homogeneous solution is formed. For work-up, the reactionmixture is poured onto ice-water and extracted three times withmethylene chloride. The organic phase is washed with sodium bicarbonatesolution, dried with magnesium sulfate and concentrated. This gives 11.4g of crude product which is used for the next step without furtherpurification.

EXAMPLE 7

[0187] Preparation of3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole(process step f))

[0188] At at most 45° C., 11.3 g (100 mmol) of 30% strength hydrogenperoxide are added dropwise to a solution of 11.4 g (40 mmol) of3-(3-bromo-2-methyl-6-methylthiophenyl)-4,5-dihydroisoxazole and 400 mgof sodium tungstate hydrate in 100 ml of glacial acetic acid. Thereaction mixture is stirred at room temperature overnight. For work-up,the mixture is poured onto ice-water and extracted with methylenechloride, and the organic phase is washed with aqueous sodium sulfitesolution, dried over magnesium sulfate and concentrated. Yield: 9.6 g.For purification, the product can be recrystallized from 65 ml ofisopropanol.

[0189] Yield: 7.7 g (50% over 2 steps), m.p.: 137-139° C.

EXAMPLE 8

[0190]1-Methyl-4-(3-(4,5-dihydroisoxazol-3-yl)-2-methyl-4-methylsulfonylbenzoyl)-5-hydroxypyrazole(process step g)-variant A)

[0191] 2.2 l of 1,4-dioxane, 100 g (0.315 mol) of3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole, 30.82g (0.315 mol) of 1-methyl-5-hydroxypyrazole, 87 g (0.63 mol) ofpotassium carbonate, 63.5 g (0.63 mol) of triethylamine and 11.2 g(0.016 mol) of bis(triphenylphosphine)-palladium dichloride were addedto a 3.5 l autoclave. The autoclave was then flushed twice withnitrogen, a carbon monoxide pressure of 10 kg/cm² was applied and themixture was heated with stirring to 130° C. The carbon monoxide pressurewas increased to 20 kg/cm² and the mixture was stirred at 130° C. for 24h. The mixture was then concentrated under reduced pressure and theresidue was taken up in water. The aqueous phase of pH 11 was extractedwith dichloromethane. The organic phase is discarded. The aqueous phaseis adjusted to pH 4 using 18% strength hydrochloric acid. Theprecipitate was filtered off, washed three times with water and dried at40° C. under reduced pressure. This gives 85 g of product. The filtrateis extracted with dichloromethane. The organic phase is dried withsodium sulfate, and the solvent is then removed under reduced pressure,giving a further 12.7 g of product.

[0192] Yield 97.7 g (85.6%), m.p.: 215-219° C., ¹H-NMR (CDCl₃): δ=2.38(s); 3.23 (s); 3.41 (bs); 3.74 (s); 4.61 (t); 7.37 (s); 7.64 (d); 8.16(d).

EXAMPLE 9

[0193]1-Methyl-4-(3-(4,5-dihydroisoxazol-3-yl)-2-methyl-4-methyl-sulfonylbenzoyl)-5-hydroxypyrazole(process step g)-variant B)

[0194] 2 l of 1,4-dioxane, 250 g (0.77 mol) of3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole, 77 g(0.77 mol) of 1-methyl-5-hydroxypyrazole, 269 g (1.93 mol) of potassiumcarbonate, 197 g (1.93 mol) of triethylamine, 1.39 g (0.0077 mol) ofpalladium(II) chloride and 4.12 g (0.0154 mol) of triphenylphosphinewere added to a 3.5 l autoclave. The autoclave was washed twice withnitrogen, the mixture was heated with stirring to 130° C. and a carbonmonoxide pressure of 6 kg/cm² was applied. By continuous addition ofcarbon monoxide, the carbon monoxide pressure was kept constant at 6kg/cm² and the mixture was stirred at 130° C. for 36 h. The mixture wasthen admixed with 1 l of demineralized water and the precipitatedpalladium was filtered off over a blue-band filter (pore size 2 to 3 μ)and washed with water. Dioxane, triethylamine and some of the water werethen distilled off in one step (150 mbar or atmospheric pressure). Theaqueous phase was adjusted to pH 2.5 using 20% strength sulfuric acidand stirred at 5° C. for 12 h, while the pH was being readjusted. Theprecipitate was filtered off, washed three times with water and dried at70° C. under reduced pressure. This gave 227 g of product (calc. 100%).

[0195] Yield 227 g (81%), m.p.: 215-219° C., ¹H-NMR (CDCl₃): δ=2.38 (s);3.23 (s); 3.41 (bs); 3.74 (s); 4.61 (t); 7.37 (s); 7.64 (d); 8.16 (d).

[0196] Palladium recovery rate on filter: 85-98%

[0197] Elemental analysis of the palladium that was filtered off(dried): Pd 48%, O 22%, C 11%, H 1.3%, P 0.2%, S 0.2%, Br<0.5%, Cl<0.5%,N<0.5%.

EXAMPLE 10

[0198] Preparation of4-bromo-2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline

[0199] 30 g (170 mmol) of 2-(4,5-dihydroisoxazol-3-yl)-3-methylanilineare dissolved in 400 ml of acetonitrile, and 94 g (0.68 mol) ofpotassium carbonate are added. At temperatures <30° C., 84 g (174 mmol)of tetrabutylammonium tribromide are then added a little at a time, withvigorous stirring. For work-up, the solid is filtered off with suctionand the solution is diluted with methylene chloride and extracted withwater. The solvent is stripped off and the residue is then taken upagain in methyl tert-butyl ether and washed twice with water. Theorganic phase is dried and concentrated.

[0200] Yield 20.4 g (47%) of a brown solid, m.p.: 126-130° C., purityaccording to HPLC 97%

EXAMPLE 11

[0201] Preparation of4-bromo-2-(4,5-dihydroisoxazol-3-yl)-3-methyl-benzenesulfonyl chloride

[0202] At 15° C., a solution of 9 g (35 mmol) of4-bromo-2-(4,5-dihydro-isoxazol-3-yl)-3-methylaniline in 50 ml ofglacial acetic acid is added to 15 ml of conc. hydrochloric acid. At5-10° C., a solution of 2.44 g (35 mmol) of sodium nitrite in 10 ml ofwater is then added dropwise, and the mixture is stirred at 5° C. for 1hour. This solution is then added dropwise at room temperature to amixture of a solution of 47 g (0.74 mol) of sulfur dioxide in 100 ml ofglacial acetic acid and a solution of 2.23 g (13 mmol) of copper(II)chloride in 5 ml of water. The mixture is stirred at room temperaturefor 1 hour and then poured onto 300 ml of ice-water and extracted withmethylene chloride. The organic phase is washed with water, dried withmagnesium sulfate and concentrated.

[0203] Yield 11.8 g (99%), purity according to HPLC 96%

[0204] In the working examples below, the preparation of benzaldoximesof the formula XV (process step a) is described in more detail.

EXAMPLE 12

[0205] Preparation of 2-methyl-6-nitrobenzaldoxime (variant A)

[0206] A solution of 274 g (2.6 mol) of n-butyl nitrite (97%) and 300 g(2.0 mol) of 3-nitro-o-xylene (97%) in 750 ml of dimethylformamide iscooled to from −55 to −60° C., and a solution of 522 g (4.56 mol) ofpotassium tert-butoxide in 750 ml of dimethylformamide is added dropwiseat this temperature over a period of 2.5 hours. During the addition, thecolor of the solution changes from yellow to deep red and the solutionbecomes viscous. The reaction is monitored by HPLC. For work-up,initially 300 ml of water are added and then about 300 ml of glacialacetic acid, until the pH has reached 5-6. During the addition, thetemperature increases to −10° C., and a yellow suspension is formed. Thereaction mixture is then poured onto 6 kg of ice-water and the residuethat has formed is filtered off with suction, washed with 5 l of waterand dried in a drying cabinet at 30° C. overnight. This gives 339 g of alight-beige crude product which is freed from the impurities bysuspension in about 3 l of toluene at 80-90° C. for 2 hours. Aftercooling, the product is filtered off with suction and dried. This gives276 g of 2-nitro-6-methyl-benzaldoxime.

[0207] Yield: 77%, m.p.: 190-192° C., purity (according to HPLC): 98%.

EXAMPLE 13

[0208] Preparation of 2-methyl-6-nitrobenzaldoxime (variant B)

[0209] 1200 ml of anhydrous DMF are initially charged in a 4 l reactionflask and cooled to −40° C. At this temperature, 336.5 g (4.56 mol) ofpotassium methoxide (95%) are added and suspended with stirring. Amixture of 300 g (1.92 mol) of 3-nitro-o-xylene (97%) and 274 g (2.52mol) of n-butyl nitrite (95%) is then added dropwise at −40° C. over aperiod of 7 hours (if the mixture is cooled accordingly, the duration ofthis addition can be reduced as desired). The complete conversion of thestarting material is checked by HPLC. The reaction discharge is thenadded with stirring, at from −5 to 0° C., to a mixture of 300 ml ofwater and 300 ml of glacial acetic acid. The reaction mixture is thenpoured onto 6 kg of ice-water and the solid is separated off byfiltration and washed twice with in each case 500 ml of water.

[0210] The crude product (HPLC: 96 area %) is purified by suspending themoist solid in 800 ml of toluene for 1.5 h. The solid is filtered offand dried at 50° C. in a vacuum drying cabinet.

[0211] Yield: 306 g (HPLC: 99.4 area % of product; E/Z mixture),corresponds to 85% of theory.

EXAMPLE 14

[0212] Preparation of 2-chloro-6-nitrobenzaldoxime

[0213] A solution of 4.1 g (40 mmol) of n-butyl nitrite (97%) and 5 g(29 mmol) of 2-chloro-6-nitrotoluene in 50 ml of dimethyl-formamide iscooled to from −55 to −60° C., and a solution of 3.3 g (29.5 mmol) ofpotassium tert-butoxide in 30 ml of dimethylformamide is added dropwiseat this temperature, over a period of 20 minutes. The reaction ismonitored by HPLC. For work-up, initially water is added, and thesolution is then adjusted to pH 5-6 using glacial acetic acid. Theproduct is isolated by extraction with ethyl acetate. This gives 5.7 gof 2-chloro-6-nitrobenzaldoxime. ¹H-NMR (CDCl₃): δ=8.00 (d, 1H); 7.84(s, 1H); 7.76 (d, 1H); 7.52 (t, 1H).

EXAMPLE 15

[0214] Preparation of 3-chloro-2-methyl-6-methylsulfonylbenzaldoxime

[0215] A solution of 12.7 g (119 mmol) of n-butyl nitrite (97%) and 20 g(92 mmol) of 2,3-dimethyl-4-methylsulfonylchlorobenzene in 100 ml ofdimethylformamide is cooled to from −55 to −60° C., and a solution of16.8 g (147 mmol) of potassium tert-butoxide in 70 ml ofdimethylformamide is added dropwise at this temperature, over a periodof 30 minutes. The reaction is monitored by HPLC. For work-up, initially50 ml of water are added, and the mixture is then adjusted to pH 5-6using about 30 ml of glacial acetic acid. The mixture is then pouredonto 0.7 kg of ice-water and the aqueous phase is extracted withmethylene chloride. The organic phase is washed with sodium bicarbonatesolution, dried over magnesium sulfate and concentrated. This gives 18.4g of a light-beige crude product which is purified by recrystallizationfrom about 30 ml of toluene.

[0216] Yield: 6.15 g (27%) of white crystals, m,p.: 164-168° C., purity(according to HPLC): 100%

EXAMPLE 16

[0217] Preparation of 3-bromo-2-methyl-6-methylsulfonylbenzaldoxime

[0218] A solution of 2.1 g (20 mmol) of n-butyl nitrite (97%) and 4 g(15 mmol) of 2,3-dimethyl-4-methylsulfonylbromobenzene in 50 ml ofdimethylformamide is cooled to from −55 to −60° C., and a solution of2.8 g (25 mmol) of potassium tert-butoxide in 35 ml of dimethylformamideis added dropwise at this temperature, over a period of 20 minutes. Thereaction is monitored by HPLC. For work-up, initially 10 ml of water areadded, and the mixture is then adjusted to pH 5-6 using about 9 ml ofglacial acetic acid. The mixture is then poured onto 100 ml of ice-waterand the aqueous phase is extracted with methylene chloride. The organicphase is washed with sodium bicarbonate solution, dried over magnesiumsulfate and concentrated. This gives 3.6 g of an oily crude product (90%by HPLC) which can be purified by recrystallization from toluene.

[0219] Yield: 1.22 g (27%), m.p.: 192-194° C., purity (according toHPLC): 99%

EXAMPLE 17

[0220] Preparation ofN,N-diphenyl-3-hydroxyamino-2-methyl-4-methyl-sulfonylbenzamide

[0221] a) Preparation of the Precursor

[0222] 5 g (3 mmol) of 2,3-dimethylthioanisole and 7.6 g (33 mmol) ofdiphenylcarbamoyl chloride are dissolved in 50 ml of 1,2-dichloroethaneand, at room temperature, admixed with 4.8 g (36 mmol) of anhydrousaluminum chloride. The reaction mixture is boiled at reflux for 3 hoursand then poured onto a mixture of ice and concentrated hydrochloricacid, and the aqueous phase is extracted twice with methylene chloride.The organic phase is washed with sodium bicarbonate solution, driedover, magnesium sulfate and concentrated. This gives 10.8 g of crudeproduct which is purified by silica gel chromatography using the mobilephase toluene/ethyl acetate.

[0223] Yield: 7.8 g of N,N-diphenyl-2,3-dimethyl-4-methylthio-benzamide.

[0224] At at most 45° C, 5.7 g (50 mmol) of 30% strength hydrogenperoxide are added dropwise to a solution of 7 g (20 mmol) ofN,N-diphenyl-2,3-dimethyl-4-methylthiobenzamide and 200 mg of sodiumtungstate hydrate in 50 ml of glacial acetic acid. The mixture isstirred at room temperature overnight. For work-up, the mixture ispoured onto ice-water and extracted with methylene chloride, and theorganic phase is washed with aqueous sodium sulfite solution, dried overmagnesium sulfate and concentrated.

[0225] Yield: 7.4 g ofN,N-diphenyl-2,3-dimethyl-4-methylsulfonyl-benzamide, m.p.: 155-165° C.

[0226] b) Preparation ofN,N-diphenyl-3-hydroxyimino-2-methyl-4-methylsulfonyl-benzamide

[0227] A solution of 0.7 g (6.9 mmol) of n-butyl nitrite (97%) and 2 g(5.3 mmol) of N,N-diphenyl-2,3-dimethyl-4-methylsulfonyl-benzamide in 30ml of dimethylformamide is cooled to from −55 to −60° C., and a solutionof 1.4 g (12 mmol) of potassium tert-butoxide in 10 ml ofdimethylformamide is added dropwise at this temperature, over a periodof 20 minutes. The reaction is monitored by HPLC. For work-up, initially10 ml of water are added, and the mixture is then adjusted to pH 5-6using glacial acetic acid. The mixture is then poured onto 100 ml ofice-water and the aqueous phase is extracted with ethyl acetate. Theorganic phase is washed with sodium bicarbonate solution, dried overmagnesium sulfate and concentrated. This gives 3.0 g of a partiallycrystalline crude product, which is purified by silica gelchromatography using the mobile phase toluene/acetone.

[0228] Yield: 1.0 g (46%), m.p.: 208-211° C.

Example 18

[0229] Preparation of 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde

[0230] 7.1 g of 3-bromo-2-methyl-6-methylsulfonylbenzaldoxime (23 mmol)are stirred at 65° C. in a mixture of 17 g of 5% strength hydrochloricacid, 2 g of 37% strength formaldehyde solution, 15 ml of water and 30ml of tetrahydrofuran for 32 hours. During this time, a further 3.5 g of37% strength formaldehyde solution are added in portions of 0.5 g. Themixture is then cooled to room temperature and the product is filteredoff with suction.

[0231] This gives 5.1 g (79%) of product, purity 94% (according to GC).

EXAMPLE 19

[0232] Preparation of 2-methyl-6-nitrobenzaldehyde

[0233] At 65° C., 14 g of 2-methyl-6-nitrobenzaldoxime (80 mmol) arestirred in a mixture of 55 ml of 5% strength hydrochloric acid, 37 g of37% strength formaldehyde solution, 50 ml of water and 100 ml oftetrahydrofuran for 24 hours. The phases are then separated and the darkphase is extracted with methylene chloride/water. The organic phase isdried with sodium sulfate and concentrated. This gives 10.1 g of crudeproduct, which is purified by filtration through silica gel using themobile phase toluene.

[0234] Yield: 7.2 g (54%)

EXAMPLE 20

[0235] Preparation of 2-methyl-6-nitrobenzonitrile

[0236] A solution of 16 g (150 mmol) of n-butyl nitrite (97%) and 7.7 g(50 mmol) of 3-nitro-o-xylene (97%) in 50 ml of dimethylformamide iscooled to from −5 to −10° C., and a solution of 11 g (100 mmol) ofpotassium tert-butoxide in 50 ml of dimethylformamide is added at thistemperature, over a period of 1.5 hours. The reaction mixture is stirredat room temperature for another 6 days. For work-up, the mixture ispoured onto ice-water and adjusted to pH 1 using hydrochloric acid, andthe aqueous phase is extracted with ethyl acetate. The organic phase iswashed with water, dried over magnesium sulfate and concentrated. Thisgives 8.2 g of product. The 2-methyl-6-nitrobenzonitrile can be purifiedby silica gel chromatography using the mobile phase toluene. M.p.:101-103° C.

[0237] In the working examples below, the preparation of thioethers ofthe formula VIIIa (process step d) is described in more detail:

EXAMPLE 21 a) COMPARATIVE EXAMPLE

[0238] The reaction of 2,3-dimethylaniline with dimethyl disulfide andtert-butyl nitrite in the solvent methylene chloride gives only a smallamount of the desired product C. According to GC analysis, the mainproducts were the dimerization products A and B. The dimer A is alsoformed if the reaction is carried out in excess dimethyl disulfide.

[0239] b) Process According to the Invention

[0240] The reaction of 2,3-dimethylaniline with dimethyl disulfide andtert-butyl nitrite is carried out similarly to the method described ina) using the solvent methylene chloride, but Cu powder is additionallyadded as catalyst. The reaction proceeds uniformly to give the desireddimethylthioanisole C. It was not possible to identify the dimerizationproduct A and B by GC analysis.

EXAMPLE 22 a) Comparative Example

[0241] In the reaction of 2-(4,5-dihydroisoxazol-3-yl)-3-methyl-anilinewith dimethyl disulfide and tert-butyl nitrite without catalyst,byproducts are formed. A mixture of A and B in a ratio of 2:1 accordingto HPLC area percent is obtained.

[0242] b) Process According to the Invention

[0243] The reaction is carried out similarly to the method described ina), but in the presence of Cu powder. In this case, the byproduct Acannot be detected.

EXAMPLE 23

[0244] Preparation of 2,3-dimethylthioanisole

[0245] a) 355 g (3.44 mol) of tert-butyl nitrite and 250 g of copperpowder (3.9 mol) are initially charged in 1250 ml of dimethyl disulfide,and a solution of 250 g (2.07 mol) of 2,3-dimethylaniline in 1000 ml ofdimethyl disulfide is added dropwise at 50-52° C. The mixture issubsequently stirred at 75-80° C. for 1.5 hours. For work-up, themixture is cooled, filtered off with suction through kieselguhr, and thefiltrate is washed with saturated aqueous NaHCO₃ solution.

[0246] For the purification of the product, the organic phase isseparated by distillation. Initially, excess dimethyl disulfide isremoved at atmospheric pressure. 1446 g of dimethyl disulfide(purity >97% according to GC) are recovered. The residue is thensubjected to fractional distillation under reduced pressure (0.1 mbar).

[0247] Yield: 261.3 g (83%), purity according to GC 97.5%

[0248] b) 14.2 g (124 mmol) of tert-butyl nitrite and 2.5 g (40 mmol) ofcopper powder are initially charged in 50 ml of dimethyl disulfide, anda solution of 10 g (81 mmol) of 2,3-dimethylaniline in 50 ml of dimethyldisulfide is added dropwise at 50-52° C. The mixture is subsequentlystirred at 75-80° C. for 1.5 hours. According to GC analysis, 100% ofthe aniline has been converted into the desired 2,3-dimethylthioanisole.

EXAMPLE 24

[0249] Preparation of 2-methyl-6-nitrothioanisole

[0250] 226 g (1.97 mmol) of tert-butyl nitrite and 100 g of copperpowder are initially-charged in 300 ml of dimethyl disulfide, and asolution of 200 g (1.32 mol) of 2-methyl-6-nitroaniline in 700 ml ofdimethyl disulfide is added dropwise at 50-55° C. The mixture is thenstirred at 75° C. for 8 hours. For work-up, the solid is filtered offwith suction and the solution is diluted with methylene chloride andextracted with dilute hydrochloric acid. The organic phase is washedwith saturated aqueous NaHCO₃ solution, dried over sodium sulfate,filtered off and concentrated using a rotary evaporator. Excess dimethyldisulfide is removed under oil pump vacuum. This gives 271 g (99%) of adark-red oil, purity according to HPLC 87%.

EXAMPLE 25

[0251] Preparation of 2-methyl-3,4-dimethylthiobromobenzene

[0252] 14.8 g (129 mmol) of tert-butyl nitrite and 20 g of copper powderare initially charged in 50 ml of dimethyl disulfide, and a solution of20 g (86 mol) of 4-bromo-3-methyl-2-methylthioaniline in 100 ml ofdimethyl disulfide is added dropwise at 50-55° C. The mixture is thenstirred at 50° C. for 4 hours. For work-up, the solid is filtered offwith suction and the solution is diluted with methylene chloride andextracted with dilute hydrochloric acid. The organic phase is washedwith saturated aqueous NaHCO₃ solution, dried over sodium sulfate,filtered off and concentrated using a rotary evaporator. Excess dimethyldisulfide is removed under oil pump vacuum.

[0253] This gives 19.7 g of a dark oil. The product can be purified bytrituration in methyl tert-butyl ether.

[0254] Yield 9.32 g (41%), m.p.: 70-73° C.

EXAMPLE 26

[0255] Preparation of 2,3-dimethyl-4-methylthiobromobenzene

[0256] 603 g (5.85 mol) of tert-butyl nitrite and 375 g of copper powder(5.9 mol) are initially charged in 3000 ml of dimethyl disulfide, and761 g (3.75 mol) of 4-bromo-2,3-dimethylaniline are added dropwise at50-58° C. The mixture is then stirred at 75-80° C. for 9 hours. Forwork-up, the mixture is cooled, the residue is filtered off and thefiltrate is washed with saturated aqueous NaHCO₃ solution. Forpurification of the product, the organic phase is separated bydistillation. Initially, excess dimethyl disulfide is removed underatmospheric pressure. 1870 g of dimethyl disulfide (purity >97%according to GC) are recovered. The residue is then subjected tofractional distillation under reduced pressure (0.1 mbar).

[0257] Yield: 523 g (60%), purity according to GC 99%.

EXAMPLE 27

[0258] (Reaction Sequence According to Scheme 4)

[0259] a) Preparation of 2,3-dimethylthioanisole

[0260] 355 g (3.44 mol) of tert-butyl nitrite and 250 g of copper powder(3.9 mol) are initially charged in 1250 ml of dimethyl disulfide, and asolution of 250 g (2.07 mol) of 2,3-dimethylaniline in 1000 ml ofdimethyl disulfide is added dropwise at 50-52° C. The mixture issubsequently stirred at 75-80° C. for 1.5 hours. For work-up, themixture is cooled, filtered off with suction through kieselguhr, and thefiltrate is washed with saturated aqueous NaHCO₃ solution. For thepurification of the product, the organic phase is separated bydistillation. Initially, excess dimethyl disulfide is removed atatmospheric pressure. 1446 g of dimethyl disulfide (purity >97%according to GC) are recovered. The residue is then subjected tofractional distillation under reduced pressure (0.1 mbar).

[0261] Yield: 261.3 g (83%), purity (according to GC) 97.5%

[0262] b) Preparation of 2,3-dimethyl-4-methylthiobromobenzene

[0263] 510 g (3.33 mol) of 2,3-dimethylthioanisole are initially chargedin 3 l of glacial acetic acid, and a solution of 592 g (7.4 mol) ofbromine in 1 l of glacial acetic acid is added dropwise at roomtemperature over a period of three hours. The reaction is slightlyexothermic. The reaction mixture is stirred at room temperature foranother 3.5 hours. The precipitate is then filtered off with suction andthe filtrate is admixed with 270 g of sodium acetate and concentrated.The residue is taken up in 2 l of dichloromethane and washed twice with2 l of sodium bicarbonate solution and twice with sodium chloridesolution.

[0264] The organic phase is dried over sodium sulfate and concentrated.

[0265] Yield: 615 g (79%), purity (according to GC) 99.2%.

[0266] c) Preparation of 2,3-dimethyl-4-methylsulfonylbromobenzene

[0267] At at most 100° C. (slight reflux), 266 g (2.35 mol) of 30%strength hydrogen peroxide are added dropwise over a period of 45minutes to a solution of 182 g (0.78 mol) of2,3-dimethyl-4-methylthiobromobenzene and 5.24 g of sodium tungstatehydrate in 1 l of glacial acetic acid. The reaction mixture is stirredat room temperature for another two hours. For work-up, the mixture ispoured onto 7.8 l of ice-water and stirred for another 30 minutes. Thewhite residue is then filtered off with suction and washed three timeswith water. The crystals are dried at 70° C. under reduced pressureovernight.

[0268] Yield: 195 g (94%), purity (according to GC) 100%.

[0269] d) Preparation of 3-bromo-2-methyl-6-methylsulfonylbenzaldoxime

[0270] 272.6 g of sodium ethoxide (3.8 mol) are dissolved in 0.4 l ofDMF, and a solution of 400 g of2,3-dimethyl-4-methyl-sulfonylbromobenzene (1.52 mol) and 214.6 g (1.977mol) of n-butyl nitrite in 0.8 l of DMF is added at from −20° C. to −15°C. Subsequently, another 100 g of sodium ethoxide are added. Thereaction mixture is stirred at from −20° C. to −15° C. for a total of5.5 hours.

[0271] The mixture is poured onto 4 l of ice-water and 0.4 l of glacialacetic acid and extracted with a total of 4 l of MtBE. The MtBE phase iswashed with 1 l of sodium bicarbonate solution and twice with water. Theaqueous phases are combined. The MtBE phase is concentrated using arotary evaporator and dried. The solution is concentrated and theresidue is dried using an oil pump.

[0272] Yield: 331 g (75%) of yellow-brown crystals, purity (according toHPLC) 96.6%.

[0273] e) Preparation of3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydro-isoxazole

[0274] At 60° C., a small amount of N-chlorosuccinimide is added to asolution of 50 g (171 mmol) of3-bromo-2-methyl-6-methyl-sulfonylbenzaldoxime in 200 ml ofdimethylformamide. Once the reaction has started, a total of 23.3 g (171mmol) of N-chlorosuccinimide are metered in at 40-50° C. The reactionmixture is stirred for another 30 minutes, until conversion is completeaccording to HPLC. The reaction mixture is then poured onto ice-waterand the solid is filtered off with suction, washed three times withwater and twice with n-pentane. The hydroxamic acid chloride is usedmoist and without further purification for the next reaction. The solidis dissolved in 250 ml of dichloromethane, and ethylene is passedthrough the solution with continued introduction of ethylene, 20.3 g(200 mmol) of triethylamine are added dropwise. The reaction mixture isstirred at room temperature for about 72 hours, with repeatedintroduction of more gaseous ethylene.

[0275] For work-up, the reaction mixture is washed three times withwater, and the solvent is stripped off. This gives 49 g of brownishcrystals which, according to HPLC, contain 90.6% of product. The productcan be purified by recrystallization from 200 ml of isopropanol.

[0276] Yield: 31 g (57%) of white crystals, m.p.: 133-136° C., purity(according to HPLC) 99.5%.

We claim:
 1. A process for preparing isoxazoles of the formula I

where the substituents are as defined below: R¹ is hydrogen,C₁-C₆-alkyl, R² is C₁-C₆-alkyl, R³, R⁴, R⁵ are hydrogen, C₁-C₆-alkyl, orR⁴ and R⁵ together form a bond, R⁶ is a heterocyclic ring, n is 0, 1 or2; which comprises preparing an intermediate of the formula VI

where R¹, R³, R⁴ and R⁵ are as defined above, followed by halogenation,thioalkylation, oxidation and acylation to give compounds of the formulaI.
 2. A process as claimed in claim 1, comprising one or more of thefollowing process steps: a) reaction of a nitro-o-methylphenyl compoundof the formula II

 in which the radical R¹ is as defined above with an organic nitriteR—ONO in the presence of a base to give an oxime of the formula III

 in which the radical R¹ is as defined above; b) cyclization of theoxime of the formula III with an alkene of the formula IV

 in which R³ to R⁵ are as defined in claim 1 in the presence of a baseto give the 4,5-dihydroisoxazole of the formula V

 in which R¹ and R³ to R⁵ are as defined in claim 1; c) reduction of thenitro group in the presence of a catalyst to give the aniline of theformula VI

 in which R¹ and R³ to R⁵ are as defined in claim 1; d) reaction of theaniline of the formula VI with a dialkyl disulfide of the formula VIIR²—S—S—R²  VII  in the presence of an organic nitrite and, ifappropriate, a catalyst to give the thioether of the formula VIII

 in which R¹ to R⁵ are as defined in claim 1; e) bromination of thethioether of the formula VIII with a brominating agent to give thebromothioether of the formula IX

 in which R¹ to R⁵ are as defined in claim 1; f) oxidation of thebromothioether of the formula IX with an oxidizing agent to give theisoxazoles of the formula X

 where n is the numbers 1 or 2, g) carboxylation of the isoxazole of theformula X in the presence of a compound R⁶—OH (XI) and carbon monoxideand a catalyst giving compounds of the formula I.
 3. A process asclaimed in claim 2, wherein the carboxylation in process step g) iscarried out in the presence of carbon monoxide, a palladium catalyst, ifappropriate at least one molar equivalent of a potassium salt and ifappropriate at least one molar equivalent of a tertiary amine of theformula XIII N(R^(a))₃  XIII in which one of the radicals R^(a) can bephenyl or naphthyl and the other radicals R^(a) are C₁-C₆-alkyl, arereacted with one another [sic] at 100-140° C. and at a pressure of 1-40kg/cm².
 4. A process is claimed in claim 3, wherein the reaction iscarried out at a pressure of 5-8 kg/cm².
 5. A process as claimed inclaim 3 or 4, wherein the reaction is carried out at 110-130° C.
 6. Aprocess as claimed in any of claims 3 to 5, wherein the catalyst used isa palladium(II) salt.
 7. A process as claimed in claim 6, wherein thecatalyst used is bis(triphenylphosphane)palladium(II) chloride.
 8. Aprocess as claimed in any of claims 3 to 5, wherein the catalyst used istetrakistriphenylphosphanepalladium(0).
 9. A process as claimed in anyof claims 3 to 8, wherein the potassium salt used is potassiumcarbonate, and an amine of the formula XIII (N(R^(a))₃) is additionallyused.
 10. A process as claimed in any of claims 2 to 9, wherein thecompound XI and the compound X are employed in a molar ratio of from 1to
 2. 11. A process as claimed in any of claims 2-10, wherein, inprocess step g), the heterocyclic compound XI used is a pyrazolederivative of the formula XI.a

and [sic] R⁷ is C₁-C₄-alkyl and M is hydrogen or an alkali metal atom.12. A process as claimed in any of claims 1-11, wherein the substituentsare as defined below: R¹ is C₁-C₄-alkyl; R² is C₁-C₄-alkyl; R³,R⁴,R⁵ arehydrogen or C₁-C₄-alkyl; R⁶ is pyrazol-4-yl which may be substituted byalkyl groups and/or a hydroxyl group.
 13. A compound of the formula III

where R¹ is C₁-C₆-alkyl.
 14. A compound of the formula XII

where the radicals are as defined below: A is nitro, amino or the groupS—R²; R¹ is hydrogen, C₁-C₆-alkyl; R² is C₁-C₆-alkyl; R³, R⁴, R⁵ arehydrogen, C₁-C₆-alkyl, or R⁴ and R⁵ together form a bond.
 15. A compoundof the formula X

where the radicals are as defined below: R¹ is hydrogen, C₁-C₆-alkyl; R²is C₁-C₆-alkyl; R³, R⁴, R⁵ are hydrogen, C₁-C₆-alkyl, or R⁴ and R⁵together form a bond; n is the number 0, 1 or
 2. 16. A process forpreparing compounds as claimed in claim 15, comprising one or more ofthe process steps a)-f) set forth in claim
 2. 17. The use of compoundsas claimed in any of claims 13, 14 or 15 for preparing compounds of theformula I.
 18. A process for preparing compounds of the formula XV

in which the radicals are as defined below: X is NO₂, S(O)_(n)Ry, Rx, Ryare in each case any inert radical; m is 0, 1, 2, 3 or 4; n is 2; whichcomprises reacting compounds of the formula XVI

in which the substituents are as defined above with an organic nitriteof the formula R—O—NO, where R is an aliphatic or aromatic radical, inthe presence of a base, followed, if appropriate, by conversion of theoxime group —CH═NOH in formula XV into the corresponding aldehydes —CHO,nitrites (—CN) or nitrite oxides (—CNO).
 19. A process as claimed inclaim 18, wherein the reaction is carried out at a temperature below−20° C. in the presence of the solvent DMF.
 20. A process for preparingthioethers of the formula XIX

in which the substituents are as defined below: Rx is an inert radical,m is a number from 0 to 5, R² is C₁-C₆-alkyl, which comprises reactingan aniline of the formula XX

with a dialkyl disulfide of the formula VII R²—S—S—R²—VII in thepresence of a catalyst.
 21. A process as claimed in claim 20, whereinthe catalyst used is copper powder or elemental copper.
 22. A compoundof the formula XV

in which the radicals are as defined below: X is S(O)_(n)Ry, R¹ ishydrogen, C₁-C₆-alkyl, halogen, C₁-C₆-alkoxy, C₁-C₆-alkylthio, Rx [sic]is an inert radical, Ry [sic] is any radical selected from the groupconsisting of hydrogen, chlorine and bromine and located on the phenylring in the position para to group X, m is 1, n is 0, 1 or
 2. 23. Aprocess for preparing compounds IX or X using one of the processes asclaimed in claim 18 and 20.